Xtandi sales set to surge following approval in pre-chemotherapy setting for mCRPC.
By Colin White, Lead Analyst
15 September 2014
I am the Lead Analyst for Oncology at Datamonitor Healthcare. I joined Datamonitor in 2009, having previously worked as ...
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Xtandi has gained US approval in the pre-chemotherapy setting for metastatic castration-resistant prostate cancer
On 10 September 2014, Xtandi (enzalutamide; Medivation/Astellas) gained US Food and Drug Administration (FDA) approval for the treatment of all patients with metastatic castration-resistant prostate cancer (mCRPC) following a priority review based on the results of the Phase III PREVAIL trial (Astellas press release, 2014a). Xtandi’s approval in the pre-chemotherapy setting for mCRPC will enable the drug to take further market share from Johnson & Johnson’s Zytiga (abiraterone acetate) and will lead to an upsurge in sales. In the absence of a head-to-head study, the secondary endpoint data which have been included on Xtandi’s new label could help to sway physicians who are considering switching from Zytiga.
The Phase III PREVAIL study (ClinicalTrials.gov identifier: NCT01212991) enrolled 1,700 chemotherapy-naïve patients with metastatic prostate cancer whose disease progressed despite treatment with androgen deprivation therapy. The trial was designed to evaluate an oral, once-daily, 160mg dose of Xtandi versus placebo. The final dataset revealed for the first time statistically significant co-primary endpoints and a drug safety profile indicating high patient tolerability (Astellas press release, 2014b; Medivation press release, 2014). Men treated with Xtandi experienced a 17.2-month delay, over twice as long as the 8.2-month delay experienced with Zytiga treatment (Astellas press release, 2014b; Medivation press release, 2014). The Independent Data Monitoring Committee recommended the study be stopped in late 2013 and patients treated with placebo be offered Xtandi after an interim analysis showed that patients treated with Xtandi had a 30% reduction in the risk of death (hazard ratio, 0.70; p<0.0001) and an 81% reduction in the risk of radiographic progression or death (hazard ratio, 0.19; p<0.0001) (Astellas press release, 2013; Medivation press release, 2013).
Xtandi is an androgen receptor signaling inhibitor that inhibits the androgen receptor (AR) at three distinct points in the signaling pathway (Astellas, 2013). The drug competitively inhibits binding of the androgens to the AR, AR nuclear translocation, and association of the AR with DNA (Tran et al., 2009). In preclinical studies, Xtandi was shown to provide a more complete suppression of the AR than Casodex (bicalutamide; AstraZeneca) (Longo, 2010).
Xtandi will compete head to head with Johnson & Johnson’s Zytiga as a treatment for mCRPC. Zytiga was approved for the treatment of mCRPC patients who have not received prior chemotherapy in December 2012 in the US and in January 2013 in the EU (FDA news release, 2012; Johnson & Johnson press release, 2013).
The results of the Phase III studies of Xtandi and Zytiga in chemotherapy-naïve mCRPC patients are shown in the table below.
Phase III studies of Xtandi and Zytiga in chemotherapy-naïve mCRPC patients
|Xtandi PREVAIL||Zytiga AA-302|
|Number of patients||1,717||1,088|
|Median survival study arm||32.4 months (calculated)||35.3 months|
|Median survival control arm||30.2 months (calculated)||30.1 months|
|Median survival difference||2.2 months (calculated)||5.2 months|
|p-value||p≤0.0001 (statistically significant)||p<0.0151 (not statistically significant)|
|Median rPFS study arm||13.8 months||16.5 months|
|Median rPFS control arm||3.9 months||8.3 months|
|rPFS = radiographic progression-free survival|
Source: Medivation press release, 2013; Ryan et al., 2013; Xtandi prescribing information, 2014
These trial results may influence physicians’ decisions to use one of the treatments over the other, but in the absence of a head-to-head study, a true comparison of the clinical efficacy of these treatments is not possible. The choice of treatment may therefore come down to other clinically relevant factors such as the need for concomitant steroid use or the time to initiation of cytotoxic chemotherapy.
The PREVAIL study met its primary endpoints, but it may be the secondary endpoints included on Xtandi’s new label – the time to initiation of cytotoxic chemotherapy and the median time to first skeletal-related event – that provide points of differentiation with Zytiga and boost Xtandi’s sales. The median time to initiation of cytotoxic chemotherapy was 28.0 months in the Xtandi arm versus a median of 10.8 months in the placebo arm. The median time to first skeletal-related event was 31.1 months in the Xtandi arm versus 31.3 months for patients in the placebo arm (Xtandi prescribing information, 2014). These data strengthen the case for using Xtandi in the pre-chemotherapy setting and could help to persuade some physicians that are considering switching from Zytiga.
Posted in Oncology.